2. Academic Validation
  3. An Unusual Binding Model of the Methyl 9-Anilinothiazolo[5,4-f] quinazoline-2-carbimidates (EHT 1610 and EHT 5372) Confers High Selectivity for Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases

An Unusual Binding Model of the Methyl 9-Anilinothiazolo[5,4-f] quinazoline-2-carbimidates (EHT 1610 and EHT 5372) Confers High Selectivity for Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases

  • J Med Chem. 2016 Nov 23;59(22):10315-10321. doi: 10.1021/acs.jmedchem.6b01083.
Apirat Chaikuad 1,  Julien Diharce 2,  Martin Schröder 3,  Alicia Foucourt 4,  Bertrand Leblond 5,  Anne-Sophie Casagrande 5,  Laurent Désiré 5,  Pascal Bonnet 2,  Stefan Knapp 1 3,  Thierry Besson 4
Affiliations

Affiliations

  • 1 Target Discovery Institute (TDI), and Structural Genomics Consortium (SGC), University of Oxford , Old Road Campus Research Building, Oxford OX3 7DQ, U.K.
  • 2 Institut de Chimie Organique et Analytique, UMR CNRS-Université d'Orléans 7311, Université d'Orléans , BP 6759, Orléans 45067 Cedex 2, France.
  • 3 Institute of Pharmaceutical Chemistry and Buchman Institute for Life Sciences, Goethe-University , Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany.
  • 4 Normandie Univ, UNIROUEN, INSA Rouen, CNRS , COBRA UMR 6014, 76000 Rouen, France.
  • 5 Diaxonhit , 63-65 Boulevard Masséna, 75013 Paris, France.
PMID: 27766861 DOI: 10.1021/acs.jmedchem.6b01083
Abstract

Methyl 9-anilinothiazolo[5,4-f]quinazoline-2-carbimidates 1 (EHT 5372) and 2 (EHT 1610) are strong inhibitors of DYRK's family kinases. The crystal structures of the complex revealed a noncanonical binding mode of compounds 1 and 2 in DYRK2, explaining the remarkable selectivity and potency of these inhibitors. The structural data and comparison presented here provide therefore a template for further improvement of this inhibitor class and for the development of novel inhibitors selectively targeting DYRK kinases.

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